Intra-pocket drug delivery devices for treatment of periodontal diseases

ABSTRACT

Therapeutic agent delivery devices and methods for using them in treatment of dental disease are disclosed. In the treatment of periodontal disease, a therapeutic agent such as tetracycline mixed in a polymeric matrix such as ethylene vinyl acetate copolymer is packed into the area to be treated and kept in place for a suitable time, during which the therapeutic agent diffuses out of the polymeric matrix, providing continuous therapy for the treatment site.

This application is a continuation-in-part of application Ser. No.539,823, filed Oct. 7, 1983, now abandoned.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention pertains generally to products and processes for treatingdiseases of the mouth, and particularly, to treatment of periodontaldiseases.

2. Description of the Prior Art

Periodontal disease is a condition caused by a pathogenic microbialecology established within the gingival sulcus which deepens to become aperiodontal pocket. This microbial ecology, located deep within theperiodontal pocket, differs greatly from that of the superficial oralenvironment by being more anaerobic, having a larger number of Gramnegative organisms, and having a greater proportion of motile species.

Several factors impede the diffusion of medicinal agents when applied tothe superficial periodontal tissues. Anatomically, the gum tissue isclosely adapted to the neck of the teeth, mechanically restricting thediffusional pathway. In addition, a fluid termed gingival crevice fluid,with the approximate composition of plasma, permeates the periodontalenvironment and is continually produced by the diseased periodontaltissues at a rate of 10 to 100 microliters per hour. This fluid,emanating from the diseased pocket lining, creates a net outward flowfurther impeding the introduction of medications from superficiallyapplied drug delivery devices. These interferences are sufficientlyeffective to insulate the pocket environment to the extent that salivadoes not penetrate, and topically applied medicinal agents have beenfound largely ineffectual in the treatment of established periodontitis.

Although mouth rinses may be effective in the reduction of superficialgingivitis resulting from poor home care procedures, the effectiveradius of action of these agents does not extend to the periodontalpocket. Introduction of antibacterial agents in solution form into theperiodontal pocket is similarly ineffective due to the rapid clearanceof such agents so that the duration of contact at the active site isminimal.

Conventional therapy for periodontal diseases, as first enunciated byPierre Fauchard in 1746 in his book entitled "The Surgeon Dentist, aTreatise on Teeth," involves the mechanical removal of bacterial plaquesand accumulations from the periodontal pocket at periodic intervals.This may include periodontal surgery to achieve access and to recontourdamaged tissues. These procedures require a high degree of technicalexpertise from the practioners of the art, are expensive, and oftenresult in pain, extensive bleeding, and general discomfort on the partof the patient so treated. Since these procedures provide, at best, onlytemporary reduction in bacterial populations, they must be repeated atregular intervals to be effective. As discussed by Lindhe and coworkersin "Healing Following Surgical/Non-Surgical Treatment of PeriodontalDisease" in the Journal of Clinical Periodontology, vol. 9, pages115-128, the frequency of repetion needed for optimal results may be ashigh as once every two weeks.

Methods for administering drugs for periodontal therapy have heretoforelargely been concerned with superficial application. For example,long-acting capsules or tablets held in the mouth (see U.S. Pat. No.3,911,099); buccal implants for releasing drugs into the saliva (seeU.S. Pat. No. 4,020,558); topically applied gels (see U.S. Pat. No.3,679,360); topically applied drug-containing bandages (see U.S. Pat.No. 3,339,546); a drug-containing plastic hardenable mass (see U.S. Pat.No. 3,964,164); a medicated periodontal dressing (see U.S. Pat. No.3,219,527); a topical dressing composed of a finely divided particulatecarrier and suspended medicinal agents (see U.S. Pat. No. 3,698,392); abandage for covering moist mucosal surfaces (see U.S. Pat. No.3,339,546); a microencapsulated liquid droplet formation for topicalapplication to the gums of dogs and other animals (see U.S. Pat. No.4,329,333); and foam-film devices containing medication (see U.S. Pat.No. 3,844,286). In addition, several fibrous forms for superficialmedication have been described, including impregnated or drug-releasingforms of dental flows (see U.S. Pat. Nos. 3,417,179, 2,667,443,2,748,781, 3,942,539); solid absorbable fibers of polyglycolic acid withmedicants incorporated therein (see U.S. Pat. No. 3,991,766); andcellulose acetate hollow fibers (see U.S. Pat. No. 4,175,326).

Systemic antibiotic therapy for periodontal infections has also beenused. In this instance, the objective is to eliminate or suppess growthof specific pathogenic species. Systemic administration of antibioticsstarts by selection of the antibiotic with appropriate antibacterialspectrum. Thus, for example, one might administer penicillin toeliminate Gram positive anaerobe infections, metranidazole to eliminateGram negative anaerobe infections, and tetracycline to eliminateactinobacillus infections. If effective, specific organisms sensitive tothe relatively low concentrations of antibiotic achieved by this mode oftherapy (ca. 2-10 ug/ml) will be selectively eliminated. Because of thelow concentrations of antibiotic achieved by systemic administration andthe relative high levels of bacterial resistance associated withperiodontal pathogens, the clinical success of this mode of therapy hasbeen poor, as discussed by Genco in "Antibiotics in the Treatment ofHuman Periodontal Diseases," in J. Periodontology, vol. 52, pages546-558 (1981).

Thus, it appears that none of the previously disclosed procedures hasled to an acceptable system for delivering optimally effective levels ofantibacterial substances to the site of periodontal disease activity. Inaddition, it appears that delivery of optimal concentrations of anymedicinal agent to disease sites within the periodontal pocket has notbeen addressed.

SUMMARY OF THE INVENTION

A therapeutic agent delivery device is placed within the periodontalpocket in such a manner that the diseased pocket regions come inintimate contact with it. The active agent is thus released at the siteof disease, eliminating the variability inherent in long diffusionalpathways associated with superifical or systemic treatments. Aperiodontal pack or other mechanical retaining system keeps the deliverysystem in this optimal position for the desired period of time. Bydesigning release characteristics of the drug delivery system to providesustained delivery over a period of days to months, a duration ofcontact and drug concentration is achieved which results in completeinhibition of all bacterial growth within the periodontal pocket. Uponremoval of the therapeutic agent delivery device and the mechanicalmaintenance device, the periodontal pocket, now devoid ofmicroorganisms, will repopulate in large part from the adjacent oralenvironment, a microbial population which constitutes organisms of lowpotential pathogenicity in the periodontal environment. As a result ofthe altered microbial population, clinical signs of healing areevidenced, including decreased redness, decreased bleeding, reduction ofhalitosis, elimination of suppuration, elimination of pain, andregeneration of lost connective tissue support for the tooth.

The design and application of devices which employ this therapeuticprinciple represent a novel approach to the treatment of periodontaldisease with the advantages of longer-lasting effectiveness and lesspain in application than conventional therapeutic procedures. Atherapeutic agent delivery and maintenance system suitable forcontinuously delivering a pharmacologically-effective level oftherapeutic agent to the site of a periodontal infection within aperiodontal pocket and maintaining it there includes therapeuticmaterial and biocompatible polymeric material having a glass transitiontemperature less than 37° C. The polymeric material contains thetherapeutic material impregnated in the polymeric matrix. The polymericmaterial is permeable to the therapeutic material so that the latter candiffuse out over a substantial period of time. The polymeric matrixcontaining the therapeutic agent is in the form of a fiber having adiameter in the range from 0.1 to about 1 mm, and this fiber issufficiently flexible and formable to conform readily to the periodontalsite to be treated. Included as part of the therapeutic agent deliveryand maintenance system is an appropriate means for maintaining thetherapeutic agent-containing delivery device within the periodontalpocket in contact with the site to be treated. This function isperformed by a periodontal pack or other suitable mechanical deviceswhich in use are placed over the top of the periodontal pocket betweenthe gum and the tooth, and maintain the fiber within the pocket whilesimultaneously limiting diffusion of therapeutic agent from theperiodontal pocket.

A method for treating periodontal disease employing the claimedtherapeutic agent delivery and maintenance system involves placing theabove-described fiber-shaped therapeutic agent delivery device within aperiodontal pocket directly in contact with the infected site to betreated, and maintaining it there for a predetermined time of treatmentby using a retaining device separate from the therapeutic agent deliverydevice to cover the top of the periodontal pocket and the fiber therein,this retaining device also simultaneously serving to limit diffusion ofthe therapeutic agent from the pocket.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates a therapeutic agent delivery device (1) designed tolie totally within the periodontal pocket between gum and tooth. It isheld in place by mechanical locking, by elastic retention, by adhesiveproperties intrinsic to the plastic, or by a suitable adhesive. Thisdelivery system is in contact with saliva (2), to which some of thetherapeutic material can diffuse.

FIG. 2 illustrates a form of therapy in which an inert conformingdressing (3) overlies the delivery device (1) to hold the device inplace and limit diffusional loss of the therapeutic agent into thesalivary compartment.

FIG. 3 illustrates an alternative form of mechanical retention, in whichan elastic band of bicompatible material (4) serves to occlude thepocket orifice and mechanically retain the delivery device.

FIG. 4 illustrates an alternative form in which an anular formed elastictherapeutic agent delivery device with a diffusion-limiting outersurface is designed to lie wholly or in part in a shallow periodontalpocket or sulcus.

DETAILED DESCRIPTION OF THE INVENTION

The invention relates to a method for treating periodontal disease bymeans of a therapeutic agent delivery device placed within theperiodontal pocket so that release of the therapeutic agent occurs inthe immediate vicinity of the disease process. As the volume ofdistribution is limited to the total volume of gingival crevice fluidproduced within the periodontal pocket, relatively high concentrationsof therapeutic agent are developed in the pocket by devices with smalltherapeutic agent reservoir capacities. The small amount of therapeuticagent required under these conditions, typically a few milligrams,greatly reduces the effect of the therapeutic agent at distal siteswithin the body, thereby greatly decreasing the potential for systemicside effects. By establishing local concentrations of an antibacterialagent sufficient to inhibit growth of all bacteria within the pocket,development of drug resistant strains in minimized. The potential forencouraging the development of drug-resistent pathogens is furtherminimized by the relatively short duration required to achieve thedesired effect, typically on the order of three to ten days. By thisprocedure, therapeutic agent delivery devices containing a fewmilligrams of therapeutic agent are capable of rendering effects greaterthan would be expected by the same drug used at much higher doses byother routes of administration. This principle results in anunexpectedly high degree of effectiveness from the comparatively smallamount of drug utilized.

The use of a periodontal dressing or other mechanical retaining and/ordiffusion-limiting device further enhances therapeutic effectiveness.This aspect of the method of treatment has the primary function ofmaintaining the delivery device in an optimal position to render itseffect. A second function is to reduce diffusion of therapeutic agentand therefore reduce loss of the agent into the saliva. The restrictionof therapeutic agent diffusion into saliva further reduces possible sideeffects which could conceivably occur in the oral cavity or in thegastrointestinal tract.

The local delivery devices useful in the invention comprise therapeuticmaterials in a matrix of bicompatible semipermeable polymeric material.By proper selection of the polymeric material and therapeutic material,blends may be obtained from which the therapeutic material will diffuseat a controlled rate over selected periods of time.

A wide variety of semipermeable biocompatible natural or syntheticpolymers, such as collagen, cellulosic polymers, glycolic acid polymers,methacrylate polymers, ethylene vinyl acetate polymers, ethylene vinylalcohol copolymers, polycaprolactone, etc., may provide the polymericsubstance for the local delivery device. Additionally, polyurethanes andpolylactides may be employed. These materials may be fabricated into avariety of shapes, including slabs, strips, films, ribbons, or fibers,and may have various consistencies, including solids, gels, plastic,granular aggregates, microsphere preparations, and spongy forms capableof being formed or introduced into the periodontal pocket.

The therapeutic agent delivery device is preferably in the shape of afiber having a diameter of about 0.1 to about 1 mm. For best results,this fiber should be sufficiently formable and flexible to conform tothe site to be treated, and this requirement in turn makes it necessaryto use soft polymers, typically having glass transition temperatures Tgless than about 37° C. Preferred polymers useful in the invention haveglass transition temperatures less than about 32° C., while a particularethylene vinyl acetate copolymer employed in trials and found highlyefficacious has a glass transition temperature less than 28° C. Thoseskilled in the art will known that the glass transition temperature isthat temperature below which the molecules of the polymer are restrictedin their freedom of rotational motion, thereby causing the polymer to berather stiff, and above which the molecules of the polymer have acquiredsufficient thermal energy for isomeric rotational motion or forsignificant tortional oscillation to occur about most of the bonds inthe main chain which are capable of such motion, thus causing thepolymer to be soft and flexible. Polymers having glass transitiontemperatures below body temperature (approximately 37° C.) areconformable, relatively soft, and flexible, but on the other handexhibit quite low tensile strengths. Thus, for example, such low glasstransition value materials are not suitable for use in applicationswhere any substantial degree of strength is required, such as formanufacture of sutures or fabrics. Although products such as sutures andfabrics have been manufactured of synthetic polymeric fibers containingcertain antibacterial agents, such products are made using polymericmaterials having glass transition temperatures above body temperature,to assure sufficient strength.

Table I below compares the physical properties of the polymeric materialethylene vinyl acetate, characterized by a low transition temperature,with three polymers having high glass transition temperatures and usedfor their structural advantages. Clearly, low glass transitiontemperatures are associated with low values of tensile strength andtensile modulus, and with correspondingly high values of elongation atbreak. In other words, a material having a low glass transitiontemperature is not very strong and stretches significantly beforebreaking. By contrast, the data shown for polyethylene terephthalate,polytetrafluoroethylene, and polyamides illustrates that materialshaving glass transition temperatures of 40° C. and above havesubstantially higher tensile strengths and tensile modulus values andsubstantially lower values of elongation at break than low glasstransition materials. Most commercially available sutures are made ofthe latter four materials listed in the first column of the table, inkeeping with the demonstrated high strength of these materials.Polymeric materials for use in the fibers of the present invention,however, should not be made of polymers having glass transitiontemperatures above body temperature (37° C.) because such fibers are toostiff and inflexible to be easily folded and packed into a periodontalpocket, and if forced into such a pocket would produce discomfort, andwould adapt poorly to the contours of a periodontal pocket. In addition,such fibers would be difficult to pack into the pocket in the firstinstance because of their inflexibility.

                  TABLE I                                                         ______________________________________                                                Glass                       Tensile                                           Transition                                                                            Tensile   Elongation                                                                              Modulus                                           Temp.   Strength  at break  (psi at                                           (°C.)                                                                          (psi)     (%)       23° C.)                            ______________________________________                                        Ethylene  <28         650     1450       300                                  vinyl acetate                                                                 (Elvax 40)                                                                    Polyethylene                                                                            67        25,000     75      20,400                                 terephthalate                                                                 (Dacron)                                                                      Polytetra-                                                                              126       39,200    200-400  4,210                                  fluoroethylene                                                                (Teflon)                                                                      Poly amides                                                                   Nylon 6   40-87     11,600    20-25   435,000                                 Nylon 66  50        13,050    20-25   479,000                                 Polypropylene                                                                           30-80     4,300-5,600                                                                             500-900 150,000-                                                                      249,000                                 ______________________________________                                    

It is recognized that in the fabrication of local delivery devices,certain inert substances may be included to modify the deliverycharacteristics or serve as carriers of the active agent, includingsolvents, suspending agents, surfactants, viscosity-controlling agents,complexing agents, antioxidants, antibacterials, and otherpharmaceutically acceptable materials which may be employed tosolubilize or stabilize the materials in the polymeric matrix andcontrol the rate of permeation or the action of the materials afterpermeation.

This invention is not limited to the use of antibacterial agents alone.A wide variety of therapeutic agents may be used in the invention. Sometherapeutic agents which are amenable to delivery by this means and arepotentially of value for periodontal therapy, incude (but are notlimited to) antibacterial agents such as iodine, sulfonamides,mercurials, bisbiguanides, or phenolics; antibiotics such astetracycline, neomycin, kannamycin, metranidazole, or canamycin;anti-inflammatory agents such as indomethacin, euginol, orhydrocortisone; immune-suppressive or stimulatory agents such asmethotrexate or levamasole; dentinal desensitizing agents such asstrontium chloride or sodium fluoride; odor masking agents such aspeppermint oil or chlorophyll; immune reagents such as immunoglobulin orantigens; local anesthetic agents such as lidocaine or benzocaine;nutritional agents such as amino acids, essential fats, and vitamin C;antioxidants such as alphatocopherol and butylated hydroxy toluene;lipopolysaccharide complexing agents such as polymyxin; or peroxidessuch as urea peroxide. It is recognized that in certain forms oftherapy, combinations of these agents in the same delivery system may beuseful in order to obtain an optimal effect. Thus, for example, anantibacterial and an anti-inflammatory agent may be combined in a singledelivery system to provide combined effectiveness.

The means for mechanical maintenance of the delivery system (hereafter,maintenance system) generally serves not only to hold the therapeuticagent delivery device in place, but also to prevent or reduce diffusionof the therapeutic agent out of the periodontal pocket. It can take avariety of forms; for example, an inert periodontal dressing, an elasticband of suitable biocompatible material, an elastic sheet, an adhesivefilm or gel such as n-butylcyanoacrylate, or a metallic or polymericcover. It may be biodegradable, thus eventually allowing the therapeuticagent delivery device to be washed out of the periodontal pocket bygingival fluid flow, thereby terminating therapy. In addition, it mayitself provide a therapeutic agent delivery function which could, forexample, serve to decrease bacterial or fungal accumulations, reducelocal inflammation, or mask mouth odors. The maintenance system can befastened in place by any suitable means, including self-adhesion,melting, cementing, crimping, etc.

The maintenance system may also be intrinsic to the therapeutic agentdelivery device for example, where the delivery device itself hasadhesive properties or possesses a springiness which would cause it tobe retained in the periodontal pocket once it has been inserted into thepocket in a compressed state.

Experimental determination of the concentration of tetracyclinenecessary to suppress the growth of all cultivable periodontalmicroorganisms:

Samples containing periodontal organisms taken from deep periodontalpockets of 5 patients were transferred to 10 ml of pre-reduced Ringer'ssolution, dispersed by 10 seconds of sonic oscillation at an amplitudeof 10 microns, and dilutions of 1:20, 1:100, and 1:1000 were prepared.One-tenth milliliter of each dilution was streaked on trypticase soyagar containing 5% sheep blood and 0.3 ug/ml menadione in petrie dishes.Identical plates were prepared containing 1, 8, 32, and 64micrograms/milliliter of tetracycline hydrochloride. Inoculated plateswere incubated at 35° C. in an anaerobic atmosphere at 80% nitrogen, 10%hydrogen, and 10% carbon dioxide for 5 to 7 days. Plates from dilutionsproviding separated colony growth were selected for counting todetermine the total colony forming units on primary medium and eachassociated tetracycline-containing medium. Percentages of organismsgrown at each concentration were computed. Values of 21.2%, 3.6%, 0.08%,and 0% were found on plates containing 1, 8, 32, and 64micrograms/millileter tetracycline respectively. These observationsindicate that no cultivable periodontal organisms grow at tetracyclineconcentrations of 64 micrograms/milliliter, thereby establishing theprimary design parameter for a local drug delivery system forperiodontal therapy which would suppress growth of all cultivableperiodontal microorganisms with continuous exposure of the organisms totetracycline.

Preparation of a therapeutic agent delivery device containingtetracycline as the therapeutic agent:

The chamber of a Tinius Olsen Extrusion Plastometer, with a spinneretinserted, was preheated to approximately 180° C., a temperature belowthe temperature at which tetracycline hydrochloride decomposes. It wasthen loaded with a mixture of 25% by weight of tetracyclinehydrochloride in ethylene vinyl acetate copolymer (45% vinyl acetate,melt index 7.5 g/10 min), and an extrusion ram with weights attached wasinserted into the chamber to compress the mixture while it equilibrated.After equilibration, additional weights were added to the ram to forcethe molten material through the spinneret. As the material was extruded,it cooled to form fibers which were collected in loose coils. Fibers soprepared were approximately 0.5 mm in diameter, contained about 300 ugof tetracycline hydrochloride per centimeter, and were elastic andslightly tacky.

In vitro release of tetracycline hydrochloride from ethylene vinylacetate copolymer fibers:

Triplicate samples of ethylene vinyl acetate copolymer fibers containingabout 300 ug of tetracycline hydrochloride per cm were immersed inseparate flasks containing 25 or 50 ml aliquots of deionized water, thecontainers were sealed, and the mixtures were agitated gently at 37° C.on a shaking water bath. Three-ml aliquots of the receiving fluid wereperiodically sampled and assayed for tetracycline hydrochloride bymeasuring the absorption peak at 276 nm on a Perkin-Elmer 575spectrophotometer. A 3-ml aliquot of deionized water was added to thereceiving fluid of each vessel sampled to replace the volume removed.The amount of tetracycline released was determined from a Beer's Lawplot derived from the absorbance of known concentrations of tetracyclinehydrochloride. Such tests showed that the fibers tested possessednon-linear release characteristics, sustaining delivery for 9 days underthe experimental conditions. The apparent permeability constant obtainedfrom Fick's Law of diffusion as applied to cylindrical geometry was7.1×10⁻¹² gm cm⁻¹ sec⁻¹. The approximation of drug release rate duringthe first day was 100 ug/cm, and over days 2 through 9 it wasapproximately 25 ug/cm/day.

Assay for tetracycline in gingival fluid:

Samples of gingival fluid were taken by intracrevicular samplingtechnique using filter paper strips (Harco periopaper). The relativevolume of the sample was measured by the change in dielectric constantof the filter paper (Harco Periotron) and the volume was computed from astandard response obtained from serum. The amount of tetracycline on thefilter paper sample was determined by comparing the diameter ofinhibition of growth of Bacillus cereus caused by the placement of thefilter paper on an inoculated plate with the zone of inhibition ofstandards applied in the same manner. Assay plates were made byinoculating 10 ml of Todd Hewitt broth with B. cereus and incubatingovernight at 37° C. Mueller-Hinton broth with 1.5% agar was autoclavedand cooled to 50° C. The medium was seeded by adding 2 ml of inoculum toeach 100 ml of the cooled broth-agar. Assay plates were made by pipeting7 ml of the seeded broth-agar medium into 100 mm diameter plastic petridishes. The assay was performed by placing filter paper strips witheither unknowns or standards on the solidified surface of assay platesand incubating at 37° C. overnight.

Tetracycline standards at concentrations of 500, 200, 100, 50, 25 and12.5 ug/ml were prepared from a 1 mg/ml of stock solution by dilutingwith pH 7 phosphate with 3.5% bovine serum albumin. A 0.5 ul aliquot ofeach standard was applied on identical filter paper samples using a 1 ulsyringe. The diameter of the zone of inhibition of triplicate orquadruplicate standards was measured to the nearest mm. A standardresponse function was derived by computing the linear least-squares fitof the diameter of growth inhibition as a function of the fourth root ofthe amount of tetracycline applied. Analysis of variance of regressionof the least-squares fit function for N=66 standard samples indicatedthat it provided a satisfactory fit to the data. The correlation ratioof the linear regression component was 0.951, indicating that the fittedfunction explained 95% of the observed variation, deviation fromlinearity and error accounting for less than 5% of the variation. Theaverage standard deviation of multiple standards was 0.59 mm with nosystematic dependence on the amount of tetracycline applied. The fourthorder polynominal solution of least-squares fit function was used tocompute the amount of tetracycline in gingival fluid samples from themeasured zone diameter. This assay provided a measurable response forsamples containing between 6 and 250 ng of tetracycline allowingconcentrations from 6 to 2500 ug/ml to be determined from sample volumesof 0.1 to 1.0 ul. Concentration was calculated by dividing the nanogramamount as estimated by bioassay by the volume as determined by thegingival fluid meter.

Periodontal treatment; example No. 1:

When a relatively shallow (5 mm) periodontal pocket was packed withethylene vinyl acetate copolymer containing about 300 ug of tetracyclinehydrochloride per centimeter, no covering being employed, an initialconcentration of tetracycline, as measured by microbiologic assay ofgingival fluid samples, of 650 ug/ml was established with aconcentration half-time of 13 hours. In this instance, the treatedperiodontal pocket was initially populated by approximately 10⁻⁶spirochetes per standardized microbiologic sample, bled spontaneously,and was characterized by pus formation. Following fiber placement for 10days, the spirochetal component was no longer detectable by darkfieldmicroscopy. Within one month, the periodontal pocket had healed, leavinga physiologic 3 mm sulcus. All signs of disease disappeared and the siteremained clinically healthy during subsequent examination for thefollowing year. These observations indicated that as a result ofplacement of the therapeutic agent delivery device into the periodontalpocket, a long-term clinical change was associated with a permanentalteration of the microbial ecology of the region.

Periodontal treatment; example No. 2:

The therapeutic agent delivery device of treatment Example 1 was placedinto a suppurant, deep (8 mm) periodontal pocket by forcing the fiberinto the pocket in such a manner that the irregular pocket geometry wascompletely filled with the delivery material. This region was thenoverlaid by a dressing made of zinc-oxide and eugenol. This dressingmaterial, commonly used as an intra-oral bandage by practitioners, wasmixed as a combination of liquid and powder which rapidly hardens in themouth to form an inert mass which conforms to the irregular boundariesof the neck of the tooth and adjacent gum tissue. By so doing, thetetracycline-loaded delivery device already forced deep into the pocketwas maintained in close proximity to the active disease site for a totalof 10 days. At the time of removal of the periodontal dressing and theunderlying drug delivery device the concentration of the tetracycline ingingival fluid was approximately 1000 micorgrams/milliliter (0.1%),indicating that higher levels of drug were maintained over thetherapeutic period when the delivery device is covered by a periodontaldressing.

At the time of removal, the periodontal tissues appeared less inflamed.One month later, the pocket depth measured 4 mm, representing a majorimprovement in connective tissue attachment to the tooth. Over theremaining 6 months of observation, the site continued to appearclinically healthy.

Periodontal treatment; example No. 3:

One periodontal pocket in each of 6 patients was treated as described inExample 2. Microbiologic changes associated with the treatment wereevaluated by determining the Gram staining properties of 50 randomlyselected isolates derived from blood-agar primary isolation platesincubated in an anaerobic environment. Before treatment, 56% of theorganisms isolated were Gram positive; one month later; 71% were Grampositive. These observations indicate that a major microbiologicalteration occurred as a result of the local antibacterial therapyadministered in the preceeding month. The significant change inpercentage composition indicates that an ecologic alteration hasresulted from the therapy.

It should be understood that the description and specific examplesgiven, while indicating preferred embodiments of the invention, aregiven by way of illustration only, since various changes andmodifications within the spirit and scope of the invention will becomeapparent to those skilled in the art from this description and theaccompanying claims.

What is claimed is:
 1. A therapeutic agent delivery device suitable forcontinuously delivering a pharmacologically-effective level oftherapeutic agent to the site of a periodontal infection within aperiodontal pocket, comprising a therapeutic agent selected from thegroup consisting of immune-suppressive agents, immune-stimulatoryagents, dentinal desensitizers, odor masking agents, immune reagents,antiinflammatory agents, antibacterials, anesthetics, nutritionalagents, antioxidants, lipopolysaccharide complexing agents andperoxides; and a biocompatible polymeric material having a glasstransition temperature of less than 37° C., said polymeric materialcontaining said therapeutic material impregnated therein and beingpermeable to said therapeutic material, the combination of saidtherapeutic agent and said polymeric material being in the form of afiber having a diameter of about 0.1 to 1 mm, and the polymeric materialis a polymer selected from the group consisting of collagen, glycolicacid polymers, methacrylate polymers, and polylactides.
 2. Thetherapeutic agent delivery device of claim 1 wherein the fiber has adiameter of about 0.5 mm.
 3. The therapeutic agent delivery device ofclaim 2 wherein said polymeric material contains 10 to 50 percent byweight of said therapeutic material.
 4. The therapeutic agent deliverydevice of claim 2 wherein said polymeric material for a glass transitiontemperature less than 32° C.
 5. The therapeutic agent delivery device ofclaim 2 wherein said polymeric material for a glass transitiontemperature less than 28° C.